- The leading company in genetic diagnostics Health in Code is to bring in the first Revio™ machine in Spain, which will enable large-scale high-precision (HiFi) long reads to improve detection of variants in complex regions.
- This technology provides a more comprehensive view of human genomes, which could be a game changer for patients lacking a clear diagnosis and in the field of rare diseases.
Madrid, 31/05/2024
Genetic understanding of diseases has evolved at a dizzying pace in recent years thanks to the development of DNA sequencing technologies. These are becoming increasingly powerful, making it possible to address the challenges and limitations of conventional solutions.
Although around 85% of known pathogenic variants are found in protein-coding regions, only 1–2% of the human genome is made up of these regions. Over the past few decades, the efforts of the clinical community have focused on the study of these regions. But despite the major breakthroughs in genetic diagnostics using mass sequencing tools (next-generation sequencing, NGS), the genetic basis of a large percentage of diseases remains unresolved, with resolution rates of between 25% and 50% in rare diseases. This leaves many individuals without a definitive diagnosis.
Resolving these types of clinical cases is one of the challenges the company Health in Code is working on, which is why this leading company in genetic diagnostics has reached an agreement with PacBio, becoming its first service provider in Southern Europe, to deploy HiFi long-read sequencing. To this end, it will install the first Revio™ machine in Spain, which can sequence up to 1,300 genomes per year, generating HiFi reads.
Complex genomic regions: a challenge for molecular diagnostics
Despite the breakthroughs in genome sequencing technology, there are still complex regions in the human genome that cannot be adequately analyzed using short-read sequencing techniques. These regions, which include pseudogenes, complex variants (insertions, deletions, translocations or structural variants), tandem repeat expansions and loss of heterozygosity, pose a significant challenge for precision molecular diagnostics.
PacBio technology offers a comprehensive solution to these limitations by enabling high-fidelity (HiFi) long-read sequencing. Recent studies have shown that PacBio sequencing has increased diagnostic power in previously undiagnosed families in up to 17.3% of the cases1. This is due to its high capacity to resolve structural variants (SVs) and copy number variants (CNVs), while maintaining a high level of precision (> 99%) in the detection of single nucleotide variants (SNVs), small insertions and deletions.
PacBio sequencing also permits direct epigenetic analysis without any additional steps during sample processing. This opens up new horizons for the study of diseases related to genetic imprinting, such as Prader-Willi syndrome, social-cognitive defects in Turner syndrome and multiple neoplasias associated with loss of imprinting at oncogene loci.
What’s more, sequencing with HiFi long reads is the only type that can provide accurate information on haplotypes. This information is crucial for the study of genes such as RPE65—involved in a recessive form of retinal dystrophy that can be treated with gene therapy—and the HLA gene, whose genotyping is essential for transplants.
The advantages of PacBio sequencing go beyond molecular diagnostics. Generating long reads facilitates the construction of higher-quality gene assemblies, providing a more complete and accurate representation of an organism’s DNA. This means it is also possible to identify important genetic variants and regulatory regions that are difficult to analyze using conventional techniques. With PacBio Revio™ technology, a complete sequence of chromosomes—including telomeres and centromeres—can be accurately assembled.
Adopting PacBio sequencing technology represents a major breakthrough in genetic diagnostics and basic scientific research. By overcoming the limitations of short-read platforms, PacBio opens the door to new areas of genetic diagnostics and personalized medicine that were previously unexplored. This technology has the potential to benefit thousands of families suffering from complex diseases, giving them greater clarity on the underlying causes of their disease and shortening the diagnostic odyssey awaiting them.
To this end, the Estonia National Biobank has recently chosen PacBio’s technology to sequence 10,000 whole human genomes and unlock new insights across cardiology, mental and reproductive health, drug response, cancer research and rare diseases. This project is funded by the European Commission and the Estonian government to help the country adopt personalized medicine at scale and adapt public health systems to the biology of its population, a strategy that new countries hope to join..
- Smith, J., Doe, A., Johnson, R., & Williams, P. (2024). Comprehensive Analysis of Long-Read Sequencing in Rare Disease Diagnosis. medRxiv. https://doi.org/10.1101/2024.05.03.24305331
